Efficacy of a non-peptide GLP-1 analogue, orfoglipton to induce weight loss reported in a phase 2 study

While the availability of peptides targeting GLP-1 and GIP receptors have revolutionized the management of obesity in patients with or without type 2 diabetes, peptides can easily be degraded by multiple enzymes in the stomach and the intestines as well as having low permeability across intestinal epithelium. Thus, to ensure optimal plasma therapeutic levels, majority of peptides are given by subcutaneous injections for clinical use. Where oral peptide formulations are available, such as the GLP-1 analogue, Rybelsius, patients will need to be educated properly to take their tablets on an empty stomach with minimal amount of water to ensure optimal absorption. To ensure further individualization of care especially where patients are not be able to religiously comply with instructions for oral peptide administration, data are needed regarding the efficacy and safety of the non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist. In a phase 2 study presented at the ADA meeting and simultaneously published in the New England J of Medicine,^[1] orfoglipron as a once daily oral therapy was investigated for weight reduction in adults with obesity. In this study, participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36 or 45 mg) or placebo once daily for 36 weeks. At week 26 (primary end-point), the mean change from baseline in body weight ranged from −8.6% to −12.6% across the orforglipron dose cohorts and at week 36 (secondary end-point), the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo. Importantly, the use of orforglipron led to improvement in all pre-specified weight-related and cardiometabolic measures and the adverse effect and safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. Importantly, weight loss with orforglipron did not appear to plateau at the 36-week mark in the trial and later-phase studies are currently underway to evaluate the drug for longer to assess its full efficacy. The data seemed to provide preliminary evidence that this non-peptide oral GLP-1 agonist orfogliprin produced.